Reducing occupational stress with a B-vitamin focussed intervention: a randomized clinical trial: study protocol

Stress in the workplace is an increasing problem in Australia and most Western countries. Stress related claims have steadily risen each year in all states of Australia from 1997 to 2006 [1]. Additionally, it has been estimated that occupational stress costs the Australian economy $14.81 billion per year in stress related workplace inactivity and absenteeism at work [2]. The World Health Organization (WHO) has stated that the direct cost of occupational stress in 1992 in the USA was US$42 billion [3]. The cost of high levels of Occupational Stress can be seen at personal, organizational and societal levels. Workers who experience high occupational stress are significantly more likely to make a stress-related work cover claim, use significantly more medical resources and contribute less to an organization through increased absenteeism and lost productivity. Prolonged experience of high levels of stress and not being able to meet workplace demands can lead to ‘burnout’. Workers experiencing greater mental and physical health issues are costly to treat whether the symptoms are chronic or acute, reducing the worker’s ability to return to the workplace. The WHO has claimed that in the USA some US$300 billion is lost in productivity, absenteeism and staff turn-over each year due to high levels of occupational stress (amounting to approximately 2.6% of US GDP). These data highlight the need for time and cost effective interventions to reduce occupational stress.

The US National Institute for Occupational Health and Safety (NIOSH) has argued that Occupational stress occurs when there is a discrepancy between the demands of the environment/workplace and an individual’s ability to carry out and complete these demands. Increased workplace demands diminish the ability of our body to deal with stress [4]. Additionally, poorer diets because of longer hours spent at work also result in a diminished capacity for our body to deal with stress.

B group vitamins can be found in a wide range of foods like whole grains, bananas, beans and meats. Folate/folic acid, B6 and B12 represent some of the B group vitamins. Folate, B6 and B12 vitamins are known to contribute to the regulation of healthy levels of the amino acid HCy, and share a synergistic role in the maintenance of cardiovascular and neural health, and are also vital for energy metabolism [5, 8, 9]. Cross sectional and prospective studies have identified that elevated plasma HCy levels is associated with the promotion of spontaneous cell death (apoptosis), incidence of stroke, brain atrophy, Alzheimer’s disease, bone fracture and is considered a risk factor for cerebrovascular disease [11, 12].

Folate/folic acid, B6 and B12 vitamins are essential for the methylation of HCy to methionine in the central nervous system. Methionine plays a crucial role in one-carbon metabolism; biological processes for DNA synthesis, repair and other methylation reactions [13]. If HCy is not sufficiently converted back to methionine, the methylation process will be inhibited resulting in a build-up of HCy. An elevated level of HCy increases the likelihood for oxidative stress, leading to negative events like mitochondrial membrane damage and DNA strand breakage [14, 15]. The role of HCy in disease pathogenesis remains unclear. HCy could play a direct role in the disease process or be simply a marker of folate, B6 and or B12 vitamin deficiency. However, research has identified that chronic stress depletes vitamin B6 [16] while supplementation with B6 vitamins could be a therapeutic strategy in reducing stress [17]. Therefore, one mechanism by which B group vitamin intervention may aid the reduction of stress and fatigue ratings of those in full time employment is through the uninhibited clearance of HCy.

In addition, neuroimaging studies suggest that high levels of plasma HCy and low levels of B vitamins are linked to a higher incidence of brain atrophy and degeneration [18, 19]. This type of data suggests that HCy plays a role in brain ageing, by contributing to subclinical brain changes in what we would believe to be an otherwise healthy population.

One potential pharmacological intervention to assist our bodies to cope with increased levels of stress that has received some preliminary support recently is vitamin B supplementation. Dietary deficiencies in micronutrients have been implicated in altered mood states (including work stress and psychiatric symptoms) in otherwise healthy individuals [20]. Supplementation with micronutrients to overcome these dietary deficiencies has been observed to improve perceived stress, mild psychiatric symptoms, and some aspects of everyday mood in a recent meta-analysis of studies examining short-term multivitamin supplementation [21]. These positive effects have been postulated to have occurred through alteration of biochemical processes affected by poorer dietary status through supplementation. Specifically, high doses of B vitamins have been suggested to be effective in improving mood states in both clinical and non-clinical populations.

Work stress is the result of an imbalance between the assessment of environmental demands and an individual’s resources and skills [22]. Despite the widespread use of vitamins to compensate for the busy lifestyle and irregular eating patterns that often accompany stress, there are few controlled trials directly investigating the relationship between multivitamins and psychological strain [23]. Despite strong advertising campaigns from many Vitamin companies, many of the claims do not have strong evidence. Therefore more studies are urgently required to help inform the public about the efficacy of vitamins on states such as stress which are often targeted by vitamin companies. There are a few smaller studies on this topic. Two studies using a multivitamin formula observed a reduction in stress symptoms after supplementation of just 28 and 30 days [24, 25]. Schlebusch and colleagues used a well-designed protocol, and screened for a highly stressed sample [25]. After 30 days of supplementation, significant treatment effects were evident, with the multivitamin reducing the level of anxiety and stress and improving psychological well-being. Carroll and colleagues [24] used a similar design with a smaller sample but employed more stringent exclusion criterion. Eighty male participants were supplemented over 28 days. They demonstrated significant reductions in anxiety and perceived stress in the multivitamin group in comparison to the placebo group. These participants also reported being less tired and having greater concentration compared to the placebo group. Our research centre has recently examined whether a popular multivitamin supplement available in Australia, (Blackmore’s Executive B Stress Formula) containing a complex of mostly B group vitamins, improved work related stress (the only study to address work stress variables) [23]. The duration of administration of the multivitamin in this study was 90 days, a significant increase in comparison to previous studies of 30 days of multivitamin administration [24–26]. Sixty participants, recruited from the community, completed the 3-month, double-blind, randomized, placebo-controlled trial in which personality [27], work demands, mood, anxiety and strain were assessed. The primary analysis revealed that the Vitamin B group reported significant reduction in Personal Strain (p = 0.02), from weeks 4 (M 92.10, SE 2.44) to week 12 (M 85.54, SE 2.27), while the placebo group showed a significant increase in levels of strain from week 4 (M 88.84, SE 4.33) to week 12 (M 93.44, SE 4.03).

Cross sectional and prospective studies in the elderly have revealed a positive relationship between cognitive performance and B vitamin intake, and a negative relationship between cognitive performance and B vitamin deficiency as evidenced through plasma HCy levels [28]. It is through the process of methylation reactions that B Vitamins are believed to influence cognitive performance [29]. It has therefore been postulated that the HCy lowering properties of B vitamins, could potentially mitigate the effects of cognitive decline [30, 31].

Recently, studies have emerged that have identified a link between brain atrophy, cognitive ability and B vitamin levels. For example, Smith and colleagues [32] investigated vitamin B6, B12 and folic acid supplementation with an older sample that were experiencing mild cognitive impairment, and observed that the rate of brain atrophy declined in those who consumed vitamins compared to placebo. They also observed that high brain atrophy was associated with lower cognitive test scores. Similar results were obtained by de Jager and colleagues [33], where vitamin B supplementation significantly slowed cognitive impairment over 2 years. This was especially the case in those who had high levels of plasma HCy. Promising results have also been detected with folic acid supplementation alone, where 3 years of supplementation significantly improved cognitive facets relating to processing speed, memory and attention [28]. It must be noted, however, that these studies have focussed on participants who are elderly and therefore experience cognitive decline more readily than younger individuals. It also highlights the need for better vitamin B nutrition in those who are older and working, where cognitive decline is both prevalent and occupationally detrimental.

Few randomised controlled trials have investigated the cognitive benefits of vitamin intake in younger, healthy cohorts. However, a randomized controlled study conducted by Pipingas and colleagues [34] investigated the effects of 16 weeks supplementation of a multivitamin with 138 participants aged between 20 and 50 years. While these researchers did not observe any significant improvements in cognitive ability, they noted that plasma folate, B6 and B12 levels were increased and HCy levels decreased after multivitamin supplementation.

Healthy vitamin and mineral status is paramount for healthy neurocognitive function and well-being [35]. During pregnancy it is an accepted practice for women to supplement their diet with folate. Early studies established that dietary supplementation of folic acid reduced the risk of babies being born with neural tube defects such as spina bifida and anencephaly [36]. Folic acid intake is therefore paramount during pregnancy to assist the proper closure of the foetal neural plate which under rapid development forms the spinal cord and skull.

A wide variety of neurological symptoms manifest in humans as a result of vitamin B12 deficiency. Numbness of the skin, hands or feet, muscle weakness and disjointed motor coordination are some of the symptoms indicative of sensory and motor disorders as a result of the degeneration of the spinal cord due to inadequate myelin [37]. Whereas confusion, apathy, depression and dementia like symptoms are indicative of cerebral disorders that can vary in severity and can include memory and judgement impairments [37]. When folate or vitamin B12 is insufficient, an accumulation of HCy occurs which is understood to be highly toxic to neurons and believed to be the cause of these neurological, sensory and motor symptoms described [38]. Therefore, it is suggested that consumption of vitamin B12 will address the accumulation of HCy, and in turn, alleviate the associated neurological, sensory and motor system symptoms.

Folate, B6 and B12 vitamins are the key vitamins that have a direct effect on mood and neurotransmitter regulation. Methionine is required in the synthesis of S-adenosylmethionine (SAM), solely responsible for methylation reactions in the brain [39]. The products of these reactions include the neurotransmitters related to psychological well-being such as dopamine, serotonin and norepinephrine in addition to phospholipids, proteins, DNA and myelin [29]. Furthermore, SAM is essential for the maintenance of choline as well as the production of acetylcholine in the central nervous system (important for memory and mood, skeletal muscle control, heart rate and breathing and transforming cysteine into the most abundant antioxidant in the body, glutathione) [40]. Research has established the efficacy of SAM as an anti-depressant treatment for those suffering from depression with recent reviews detailing that supplementation with SAM for four weeks or more is as effective as treatment with tricyclic antidepressants for clinical depression [41, 42]. In terms of cognitive effects, B12 vitamin and folate deficiency may cause a disruption to the SAM pathway, leading to a reduction in the production of neurotransmitters. Therefore, deficiency may have a direct effect on mood and cognitive function by virtue of these vitamins in the production of neurotransmitters [43].

A clear association exists between HCy levels and cardiovascular health [14]. An increased level of HCy has a harmful effect on the cardiovascular system through actions that promote blood clotting with platelets and the release of growth factors for vascular endothelium [44]. A reduction in the bioavailability of a powerful vasodilator, endothelial nitric oxide, may be related to vascular damage [38]. Kang and colleagues [45] reported a relationship between job-related stress, plasma HCy levels and cardiovascular risk factors in a group of 152 workers. Similarly, other researchers [17] reported a significant relationship between acute psychological stress and elevated plasma HCy levels, blood pressure and heart rate. They concluded that one mechanism, high HCy, through psychological stress may contribute to the initiation and progression of vascular disease. These findings suggest that the interrelationship between B vitamins and folate in the regulation of HCy may affect cognitive function via direct effects on the brain or indirectly via mechanisms working on the cardiovascular system. As such, examination of the effect of B-vitamin supplementation upon stress, mood, and cognitive performance alongside measurement of probable biological and neurological mechanisms of action of B vitamins should help clarify the therapeutic role of these commonly available supplements.

Given the growing incidence, cost and pervasive effects of stress in the modern workforce, the primary objective of this research is to determine whether administration of B-vitamins reduces occupational stress (or strain), burnout, and the cost of absenteeism in a population of older workers with high levels of occupational stress. We will examine the relationship between B-vitamin supplementation, workplace stress, cognitive, personality and mood measures, cardiovascular (brachial and aortic systolic and diastolic blood pressures as well as arterial stiffness), biochemical (assays to measure inflammation and safety) as well as genetic assessments (to assess stress processing) and neuroimaging measures (to investigate in vivo mechanisms of action of B vitamins) to identify the mechanisms through which B-vitamin supplementation may improve the well-being of Australian workers.

Occupational stress is a multibillion dollar problem. Effective strategies reducing occupational stress are urgently required. Dietary supplementation with B group vitamins may be an economically viable and sustainable intervention. Reducing occupational stress will have enormous benefits for decreasing stress claims, absenteeism, and increasing work productivity. Vitamin B supplementation is also likely to have additional health and quality of life benefits.